Bicyclic pyrimidine compounds and therapeutic use thereof

ABSTRACT

A pyrimidine derivative of the formula (1) or a salt thereof;                    
     has an inhibitory activity of production of Th2 type cytokines such as IL-4, IL-5, etc., and is useful as an therapeutic agent for allergic diseases, autoimmune diseases such as systemic lupus erythemathosus, etc., and acquired immunodeficiecy syndrome (AIDS) and so on.

This application is the national phase under 35 U.S.C. § 371 of PCTInternational Application No. PCT/JP99/04505 which has an Internationalfiling date of Aug. 20, 1999, published in japanese which designated theUnited States of America.

TECHNICAL FIELD

The present invention relates to pyrimidine derivatives and medicinaluses thereof. In more detail the present invention relates to pyrimidinederivatives having activities for suppression of type 2 helper T cell(Th2) immune responses and enhancement of type 1 helper T cell (Th1)immune responses and therapeutic methods for immune diseases by usingthe pyrimidine derivatives and therapeutic compositions containing thepyrimidine derivatives.

BACKGROUND ART

It is first proposed by Mosmann et al. that Lymphocytes, called helper Tcells which play the central role in immune responses are classifiedinto two subsets. They classified mouse helper T cells (Th) into Th1 andTh2 depending on the kinds of cytokines produced (J. Immunol. 136,2348-2357 (1986)).

As Th1-type cytokines, interleukin 2 (IL-2), interferon γ (IFN-γ), etc.are illustrated. As Th2-type cytokines, interleukin 4 (IL-4),interleukin 5 (IL-5), interleukin 10 (IL-10), interleukin 13 (IL-13),etc. are illustrated.

Nowadays thinking of the classification into Th1/Th2 is applied to theclassification of helper T cell subsets, and also regarding a variety ofimmune responses in the living body on the point of view of which subsetof helper T cells mainly participates, the immune responses have becometo be interpreted “immune responses on Thl-type” or “immune responses onTh2-type”, respectively.

Immune responses on Th1-type are mainly induced by cytokines such asinterleukin 2 (IL-2), interferon γ (IFN-γ), etc. produced by activatedTh1. Thus, it is known that Th1 cytokines participate to cell-mediatedimmunity such as protection mainly against infections of virus,bacteria, etc. by activation of macrophage, natural killer cells etc.,or by further activation of Th1 via IL-12 etc. produced by the activatedmacrophages.

On the other hand, immune responses on Th2-type are mainly induced bycytokines such as IL-4, IL-5, etc. produced by activated Th2. Thus, itis known that Th2 cytokines participate to humoral immunity such asproduction of antibodies (e.g. IgE class) from B cells.

Since Th2 produce cytokines such as IL-4 or IL-5 which relates toallergic reaction, as mentioned below, Th2 are suggested to be theresponsible cells on allergic reaction. For example, IL-4, a typicalTh2-type cytokine, intduces production of IgE antibodies from B cells.IL-4 also induces expression of VCAM-1 gene, which is an importantmolecule which works when eosinophils adhere to vascular endothelialcells and infiltrate into the tissue (Farumashia, 29, 1123-1128(1993)).Recently IL-4 has been paid attention as a differentiation-inducingfactor for Th2. IL-5, another Th2-type cytokine, inducesdifferentiation, migration and activation of eosinophils. Allergicinflammation is characterized in being triggered off by infiltration,activation and degranulation of eosinophils, as typical chronic airwayinflammation in asthma. Thus IL-5 is considered to be a factor inducingallergic inflammation.

Since Th2 cytokines have above properties, it is recognized that Th2control both allergic reactions of “early phase reaction” by IgEantibodies or mast cells and “late phase reaction” by eosinophils, andtherefore, Th2 are central cells in allergic inflammation. And it isconsidered that allergic diseases are caused by over expression ofTh2-type immune responses. This consideration is also supported byfindings of presence of Th2 or production of Th2-type cytokines such asIL-4, IL-5, etc. in the lesion of allergic disease, such as airway orskin.

Therefore, it is considered to be important to suppress immune responsesof Th2, in order to inhibit both ealy phase and late phase reactions, orinhibit allergic inflammatory reaction characterized with infiltrationand activation of eosinophils in the stage of fundamental source and totreat therapeutically and prophylactically general allergic diseases.Namely, if a drug is developed to suppress immune responses of Th2-type,the drug will be one for therapeutic and prophylactic agent for allergicdiseases.

In especially serious chronic asthma or atopic dermatitis among allergicdiseases, late phase reaction is considered to play an important role.However, anti-allergic agents used nowadays are mainly based onanti-histamine activity and inhibit only early phase reaction andclinical effect thereof is not satisfactory. From such viewpoints too,it has been desired to develop the drug which inhibits both early phaseand late phase reactions by suppressing immune responses of Th2 andtreats therapeutically and prophylactically for general allergicdiseases as mentioned above.

Moreover, bronchodilators, which are represented by xanthine derivativesor β-stimulants which have been used as asthma agents for long years,are known to have suppressive activity of constriction of broncho smoothmuscle by various stimulation. However, these are ineffective to chronicairway inflammation which is a basic cause for asthma. In addition, sideeffects of xanthine derivatives or β-stimulants to circulatory organsare anxious. In recent asthma therapy, as definitely shown in the guideline of WHO, asthma is taken as chronic inflammation of airway and ithas made a principal object to cure the chronic inflammation of air way.The chronic inflammation of airway in asthma is triggered off byinfiltration, activation and degranulation of eosinophils and has itspathologic characteristic feature which results in hypertrophy andfibrillation of airway-epithelium. According to the above guide line,the sole steroid inhalants effective to the chronic air way inflammationare now positioned as the first chosen medicine to asthma of more thanmiddle degree.

As a result, steroids have been often used for serious asthma and atopicdermatitis as being considered as the sole effective drugs. However, itbecomes problem that by using such steroids for long terms various sideeffects (steroid dermatitis, induced infected disease, discorticism,etc.) occur.

From the point of these views too, it has been desired to develop thedrug which selectively suppresses immune responses on Th2 and inhibitsboth early phase and late phase reactions, or inhibits allergicinflammatory reaction characterized with infiltration and activation ofeosinophils in the stage of fundamental source and is therapeuticallyand prophylactically effective for general allergic diseases.

Furthermore, when it is planned to develop the therapeutic orprophylactic drugs which have less side effects, it seems that the drugswhich suppress immune responses on Th2 as mentioned above and enhanceimmune responses on Th1 simultaneously, are more preferable asmedicines. As mentioned above, since Th1 play an important role for theliving body, namely infection-protection against virus and bacteria bymainly producing IFN-γ, the drugs which suppress the immune responses onTh2 and enhance activity of Th1 are very preferable in view ofside-effects. For example, immunosuppressives, e.g. cyclosporin or FK506are known to strongly inhibit activation of Th2. However, bothcyclosporin and FK506 show non-specific suppression against immuneresponses, namely not only inhibit activation of Th2, but also morestrongly inhibit activation of Th1. Therefore, serious side effects suchas opportunistic infection or increase of carcinogenic rate caused bysuch non-specific suppression against immune responses have beenproblem. Other non-specific immunosuppressives are also considered tohave same problems.

As mentioned above, the drug which enhances immune responses on Th1represented by production of IFNγ and suppresses immune responses on Th2represented by production of IL-4 and IL-5 simultaneously, will be atherapeutic and prophylactic agent for allergic diseases with less sideeffects.

Autoimmune diseases in the state that production of an antibody orhumoral immunity are abnormally enhanced, such as systemic lupuserythematosus are also considered to be in the state that immuneresponses of Th2 are abnormally enhanced (Medical Immunology 15, 401(1988)). Therefore, the drug which enhances immune responses of Th1 andsuppresses immune responses of Th2 is expected to become a therapeuticagent for autoimmune diseases.

Pyrimidine derivatives having general anti-virus activity are disclosedin Japanese Patent Publication A 9-301958 and Japanese PatentPublication A8-134044. However, there is no suggestion of pyrimidinederivatives of the present invention which enhances immune responses ofTh1 and suppress immune responses of Th2.

SUMMARY OF INVENTION

Under such circumstances the present inventors synthesized variouscompounds and examined them on the effect to Th1 and Th2 immuneresponses. As a result, it was found that certain pyrimidine derivativesenhance Th1 immune responses and suppress Th2 immune responses andtherefore, change the balance of Th1/Th2 into preferable direction.

That is, the present invention relates to:

[1] a pyrimidine derivative of the formula (1) or a salt thereof;

 wherein R¹ is a formula (2);

 {in the formula (2),

ring A is substituted or unsubstituted C₃₋₁₀ cycloalkane, substituted orunsubstituted C₅₋₁₀ cycloalkene, substituted or unsubstituted C₇₋₁₀bicycloalkane, or substituted or unsubstituted heterocyclic ringcontaining O atom or S atom as a heteroatom, and said S atom may formsulfinyl or sulfonyl together with one or two oxygen atoms, and

R⁴ is straight or branched C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆ alkinyl, C₃₋₆cycloalkyl, C₄₋₁₀ cycloalkyl-alkyl, or OR⁸ (R⁸ is straight or branchedC₁₋₁₀ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkinyl, C₃₋₆ cycloalkyl or C₄₋₁₀cycloalkyl-alkyl)}, or a formula (3);

 {in the formula (3),

R⁵ is straight or branched C₁₋₁₀ alkyl; C₂₋₆ alkenyl; C₃₋₆ alkinyl;straight or branched C₁₋₁₀ alkyl substituted by hydroxy, halogen atom orC₁₋₄ alkoxy; phenyl; C₃₋₈ cycloalkyl; a 5 to 7 membered saturatedheterocyclic ring containing one or two oxygen atoms as heteroatoms; orC(=O)R⁹ (R⁹ is straight or branched C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆alkinyl, C₃₋₆ cycloalkyl, C₄₋₁₀ cycloalkyl-alkyl, or OR¹⁰ (R¹⁰ isstraight or branched C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆ alkinyl, C₃₋₆cycloalkyl or C₄₋₁₀ cycloalkyl-alkyl)),

R⁶ is hydrogen atom, straight or branched C₁₋₁₀ alkyl, C₆₋₁₀ aryl,halogen atom, C₆₋₁₀ aryl substituted by C₁₋₄ alkoxy or C₁₋₄ alkyl,carbamoyl, or hydroxymethyl, and

R⁷ is hydrogen atom, or straight or branched C₁₋₁₀ alkyl},

 R² is hydrogen atom, or straight or branched C₁₋₁₀ alkyl, and

 R³ is straight or branched C₁₋₁₀ alkyl; C₃₋₆ cycloalkyl; straight orbranched C₁₋₁₀ alkyl substituted by C₁₋₂ alkylcarbamoyl, C₂₋₄dialkylcarbamoyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, C₃₋₆ cycloalkyl,hydroxy, C₁₋₄ alkylcarbonyloxy, halogen atom, amino, C₂₋₄acyl-substituted amino, C₁₋₄ alkyl-substituted sulfonylamino or C₁₋₅alkoxycarbonylamino; or a formula (4);

R¹¹—(CH₂)_(n)—  (4)

{in the formula (4), R¹¹ is phenyl, pyridyl, thienyl, or furyl and eachof them may be substituted by one or more substituents. Saidsubstituents are halogen atom, cyano, carbamoyl, C₁₋₄ alkoxy, or C₁₋₄alkyl. n is integers of 0-4, provided that n is intergers of 1-4 whenR¹¹ is phenyl.}, or

 R² and R³ taken together are C₃₋₅ alkylene or said alkylene in whichmethylene is substituted by O atom,

[2] The pyrimidine derivative or its salt of [1], wherein R³ is straightor branched C₁₋₁₀ alkyl; C₃₋₆ cycloalkyl; or

straight or branched C₁₋₁₀ alkyl substituted by C₁₋₂ alkylcarbamoyl,C₂₋₄ dialkylcarbamoyl, C₁₋₄ alkoxy, C₁₋₄ alkoxycarbonyl, C₃₋₆cycloalkyl, hydroxy, C₁₋₄ alkylcarbonyloxy, halogen atom, amino, C₂₋₄acyl-substituted amino, C₁₋₄ alkyl-substituted sulfonylamino or C₁₋₅alkoxycarbonylamino; or

 R² and R³ taken together are C₃₋₅ alkylene or said alkylene in whichmethylene is substituted by O atom,

[3] The pyrimidine derivative or its pharmaceutically acceptable salt of[1] or [2], wherein R² and R³ taken together is trimethylene ortetramethylene,

[4) The pyrimidine derivative or its pharmaceutically acceptable salt of[1] or [2], wherein R³ is straight or branched C₁₋₇ alkyl,

[5] The pyrimidine derivative or its pharmaceutically acceptable salt of[1], wherein R³ is the formula (4);

R¹¹—(CH₂)_(n)—  (4)

 wherein R¹¹ and n are the same defined above,

[6] The pyrimidine derivative or its pharmaceutically acceptable salt of[1] or [5], wherein R¹¹ of the formula (4) is pyridyl, thienyl or furyl,

[7] The pyrimidine derivative or its pharmaceutically acceptable salt of[1], [5] or [6], wherein n of the formula (4) is integers 2-4,

[8] The pyrimidine derivative or its pharmaceutically acceptable salt ofany one of [1] to [7], wherein R¹ is the formula (2);

 wherein the ring A and R⁴ are the same defined above,

[9] The pyrimidine derivative or its pharmaceutically acceptable salt ofany one of [1] to [7], wherein R¹ is the formula (3);

 wherein ring R⁵, R⁶ and R⁷ are the same defined above,

[10] The pyrimidine derivative or its pharmaceutically acceptable saltof any one of [1] to [7] or [9], wherein R⁵ is straight C₂₋₄ alkyl orstraight C₂₋₄ alkyl substituted by hydroxy,

[11]. An immunomodulator which suppresses immune responses of type 2helper T cell and enhances immune responses of type 1 helper T cell,comprising the pyrimidine derivative or its pharmaceutically acceptablesalt of any one of [1] to [10] as an active ingredient,

[12] A therapeutic or prophylactic agent for diseases in the state thatimmune responses of type 2 helper T cell are abnormally enhanced,comprising the pyrimidine derivative or its pharmaceutically acceptablesalt of any one of [1] to [10] as an active ingredient,

[13] The therapeutic or prophylactic agent of [12], wherein the diseasein the state that immune responses of type 2 helper T cell areabnormally enhanced is an allergic disease, and

[14] The therapeutic or prophylactic agent of [13], wherein the allergicdisease is asthma, allergic rinitis, or allergic dermatitis.

DETAILED EXPLANATION OF INVENTION

The present invention is explained in detail below.

Definition of Words

“Substituents R¹, R² and R³” on pyrimidine ring of the present inventionare explained as follows:

In regard to R¹,

examples of C₃₋₁₀ cycloalkane in ring A are cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc. Examples ofC₅₋₁₀ cycloalkene are cyclopentene, cyclohexene, etc. Examples of C₇₋₁₀bicycloalkane are bicyclo[2.2.1]heptane, bicyclo[2.2.1]hepta-5-ene,bicyclo[2.2.2]octane, bicyclo[2.2.2]octa-5-ene, etc. Examples ofhererocyclic ring containing O atom or S atom as a heteroatom areoxetane, thietane (trimethylenesulfide), thietane-l-oxide(trimethylenesulfoxide), thietane-1,1-dioxide (trimethylenesulfone),tetrahydrofuran, tetrahydrothiophene, tetrahydrothiophene-1-oxide,tetrahydrothiophene-1,1-dioxide, tetrahydro-4H-pyran, thian(pentamethylenesulfide), thian-1,1-dioxide (pentamethylenesulfone),thian-1-oxide (pentamethylenesulfoxide), oxepane (hexamethyleneoxide),thiepane (hexamethylenesulfide), thiepane-1-oxide(hexamethylenesulfoxide), thiepane-1,1-dioxide (hexamethylenesulfone),7-oxabicyclo[2.2.1]heptane, 7-oxabicyclo[2.2.1]hepta-5-ene, etc., and

examples of substituents of substituted cycloalkane, substitutedcycloalkene, substituted bicycloalkane and substituted heterocyclic ringin ring A are C₁₋₃ alkyl, hydroxy, C₁₋₃ alkoxycarbonyl, carboxy,carbamoyl, etc. And said substituents on the adjacent carbon atoms mayform tetramethylene bridge, or carbon atom(s) in the ring may besubstituted by carbonyl(C═O). Said substituent(s) are one or more andthe same or different. Examples of C₁₋₃ alkyl are methyl, ethyl,n-propyl, 2-propyl, etc. Examples of C₁₋₃ alkoxycarbonyl aremethoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 2-propoxycarbonyl,etc.

Examples of straight or branched C₁₋₁₀ alkyl in R², R³, R⁴, R⁵, R⁶, R⁷,R8, R⁹ and R¹⁰ are methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, heptyl,octyl, nonyl, decyl, etc.

Examples of C₂₋₆ alkenyl in R⁴, R⁵, R⁸, R⁹ and R¹⁰ are vinyl, allyl,butenyl, pentenyl, hexenyl, etc.

Examples of C₂₋₆ alkenyl in R⁴, R⁵, R⁸, R⁹ and R¹⁰ are propargyl,butinyl, pentinyl, etc.

Examples of C₃₋₈ cycloalkyl in substituents of straight or branched C₁loalkyl in R³, R⁴, R⁵, R⁸, R⁹ and R¹⁰ are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

Examples of C₄₋₁₀ cycloalkyl-alkyl in R⁴, R⁸, R⁹ and R¹⁰ arecyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, cyclohexylmethyl,cyclohexylpropyl, etc.

Examples of halogen atoms in R³, R⁵ and R⁶ are fluorine atom, chlorineatom, bromine atom, or iodine atom.

Examples of C₁₋₄ alkoxy in R³, R⁵ and R⁶ are methoxy, ethoxy, propoxy,butoxy, etc.

Preferable examples of straight or branched C₁₋₁₀ alkyl in R³ isstraight or branched C₁₋₇ alkyl, e.g. methyl, ethyl, propyl,1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, hexyl,heptyl, etc.

In regard to substituents of straight or branched C₁₋₁₀ alkyl in R³,examples of C₁₋₂ alkylcarbamoyl is methylcarbamoyl, ethylcarbamoyl,etc.; examples of C₂₋₄ dialkylcarbamoyl is dimethylcarbamoyl,methylethylcarbamoyl, diethylcarbamoyl, etc.; examples of C₁₋₄alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,2-propoxycarbonyl, etc.; examples of C₁₋₄ alkylcarbonyloxy are acetoxy,ethylcarbonyloxy, propylcarbonyloxy, etc., examples of amino substitutedby C₂₋₄ acyl are acetylamino, propanoylamino, etc.; examples ofsulfonylamino substituted by C₁₋₄ alkyl are methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino, etc.;examples of C₁₋₅ alkoxycarbonylamino are methoxycarbonylamino,ethoxycarbonylamino, propyloxycarbonylamino, butoxycarbonylamino, etc.

R¹¹ in R³ means phenyl, pyridyl, thienyl, or furyl, and each of them maybe substituted by one or more substituents. Phenyl and pyridyl arepreferable, and phenyl is especially preferable. The substituents arehalogen atoms, such as F, Cl, Br, etc., cyano, carbamoyl, C₁₋₄ alkoxy,such as methoxy, ethoxy, propoxy, etc., C₁₋₄ alkyl, such as methyl,ethyl, propyl, butyl, etc. n is integers 0-4, provided that n isintegers 1-4 when R¹¹ is phenyl. n is preferably integers 0-2, morepreferably 1 or 2.

Examples of a 5 to 7 membered saturated heterocyclic ring containing oneor two oxygen atoms as heteroatoms in R⁵ are tetrahydrofuran, oxane,1,4-dioxane, oxepane, etc.

Preferable substituents of straight or branched C₁₋₁₀ alkyl in R⁵ arehydroxy, its preferable number are one or more, and its preferableposition is 1 or 2 (position 2 or 3 on counting from amino group ofpyrimidine ring). When the substituent of straight or branched C₁₋₁₀alkyl in R⁵ is hydroxy, its position is preferably not the end positionof the alkyl chain.

Examples of C₆₋₁₀ aryl in R⁶ are phenyl, naphthyl, etc.

Preferable examples of straight or branched C₁₋₁₀ alkyl in R⁹ isstraight or branched C₂₋₄ alkyl, e.g. ethyl, propyl, 1-methylethyl,butyl, etc.

Examples of C₃₋₆ alkylene which R₂ and R₃ taken together form aretrimethylene, tetramethylene, pentamethylene, etc. They are illustratedas following formulas (4), (5) and (6);

Examples of C₃₋₅ alkylene which R₂ and R₃ taken together form in whichmethylene is substituted by O atom, are oxybismethylene,oxymethyleneethylene, oxybisethylene, etc. They are illustrated asfollowing formulas (7), (8), (9), (10), (11) and (12);

The pyrimidine derivatives of the present invention being activeingredients as medical drugs are formed into pharmaceutically acceptablesalts. As pharmaceutically acceptable salts, there are illustrated acidaddition salts and base addition salts. As acid addition salts, thereare illustrated inorganic acid salts, such as hydrochloride,hydrobromide, sulfate or phosphate, or organic acid salts, such ascitrate, oxalate, malate, tartrate, fumarate or maleate. As baseaddition salts, there are inorganic base salts such as sodium salts orcalcium salts, or organic base salts, such as meglumine salt,tris(hydroxymethyl)aminomethane salt. The pyrimidine derivatives of thepresent invention or pharmaceutically acceptable salts thereof alsoinclude solvates such as hydrates, etc.

The compounds of the formula (1) of the present invention can beprepared by the following method or according to the following method.

wherein R¹, R² and R³ are the same as defined in the formula (1) above.

PROCESS 1

The compound (22) is prepared by reacting the compound (21) withphosphorus oxychloride. The reaction may be carried out, if necessary inthe presence of a solvent. As the solvents, there are aromatichydrocarbons such as toluene or xylene. The reaction may be carried outin the presence of a reaction promoter such asN,N-dimethylaminopyridine. The reaction temperature is selected betweenroom temperature and reflux temperature of the solvent.

The compound (1) of the present invention can be prepared by reactingthe compound (22) with the compound (23). As the solvents, there arearomatic hydrocarbons such as toluene or xylene, ethers such astetrahydrofuran (THF) or dioxane, alcohols, such as ethanol, 2-propanolor butanol, or inert solvents such as dimethylformamide (DMF) oracetonitrile. The reaction is carried out, if necessary in the presenceof an organic base such as triethylamine, or an inorganic base such assodium carbonate or potassium carbonate. The reaction temperature isselected between for example, room temperature and reflux temperature ofthe solvent.

PROCESS 2

The compound (25) can be prepared by reacting the compound (24) with thecompound (23). As the solvents, there are aromatic hydrocarbons such astoluene or xylene, ethers such as tetrahydrofuran (THF) or dioxane,alcohols such as ethanol, 2-propanol or butanol, or inert solvents suchas dimethylformamide (DMF) or acetonitrile. The reaction may be carriedout, if necessary in the presence of an organic base such astriethylamine, or an inorganic base such as sodium carbonate orpotassium carbonate. The reaction temperature is selected between forexample, room temperature and reflux temperature of the solvent.

The compound (1) of the present invention can be prepared by reactingthe compound (25) with ammonia in a solvent. As the solvents, there arealcohols such as methanol or ethanol ethers such as dioxane orethyleneglycol dimethyl ether. The reaction is carried out in anautoclave at room temperature to about 200° C.

The compound (1) of the present invention can also be prepared byreacting the compound (25) with sodium azide, followed by reduction withtriphenyl phosphine. The reaction with sodium azide is carried out in aninert solvent such as DMF, etc. The reaction temperature is selectedfrom about room temperature to around the boiling point of the solvent.Reduction by triphenyl phosphine is carried out in an ether such as THF,etc. The reaction temperature is selected from about room temperature toaround the boiling point of the solvent.

The compounds of the formula (1) of the present invention andintermediates for preparing them can be purified with conventionalmethods such as column chromatography, recrysatallization, etc. As thesolvents for recrystallization there are alcohols such as methanol,ethanol or 2-propanol, ethers such as diethyl ether, esters such asethyl acetate, aromatic hydrocarbons such as toluene, ketones such asacetone, hydrocarbons such as hexane, or a mixture thereof.

In case of carrying out above reactions, protection or deprotectiontechniques are, if necessary, employed. The protection or deprotectiontechniques are in detail described in “Protecting Groups in OrganicSynthesis” by T. W. Greene and P. G. M. Wuts (1991), JOHN WILEY & SONSINC.

The pyrimidine derivatives of the present invention or pharmaceuticallyacceptable salts thereof can form solvates such as hydrates andtherefore, the present invention also includes the solvates.

When the compounds of the present invention have an asymmetric carbonatom(s), optical isomers exist and therefore, a mixture thereof and anisolated optical isomer are included in the compounds of the presentinvention. In order to purify such an optical isomer, optical resolutionis employed.

As to to optical resolution, the compounds of the present invention orintermediates thereof can be formed salts with an optically active acid(e.g. monocarboxylic acid such as mandelic acid, N-benzyloxyalanine orlactic acid, dicarboxylic acid such as tartaric acid, O-diisopropylidenetartaric acid or malic acid, or sulfonic acids such as campher-sulfonicacid, bromocampher-sulfonic acid) in an inert solvent (e.g. alcoholssuch as methanol, ethanol or 2-propanol, ethers such as diethyl ether,esters such as ethyl acetate, aromatic hydrocarbons such as toluene,acetonitrile or a mixture thereof).

When the compounds of the present invention or intermediates thereofhave an acidic substituent such as carboxy group, etc., they can beformed salts with an optically active amine (e.g. an organic amine suchas α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine,strychnine, etc.), too.

The temperature forming salts is from room temperature to the boilingpoint of the solvent. In order to increase the optical purity of thecompound, the temperature is preferably raised once to around theboiling point of the solvent. The yield can be increased, if necessaryby cooling the solvent before filtering a precipitated salt. The amountof an optically active acid or amine is about 0.5-2.0 equimoles to thesubstrate, preferably about 1 equimole. If necessary, the crystals arerecrystallized in an inert solvent (e.g. alcohols such as methanol,ethanol or 2-propanol, ethers such as diethyl ether, esters such asethyl acetate, aromatic hydrocarbons such as toluene, acetonitrile or amixture thereof) to be obtainable an optically active salt with highlyoptical purity. The obtained salt, if necessary is treated in theconventional manner with an acid or a base to obtain a free compound.

The pyrimidine derivatives of the present invention can be orally orparenterally administered. In case of oral administration, the compoundis administered in the conventional administration form. In case ofparenteral administration, the compound can be administered in a topicaladministration forms, injections, transdermal application forms or nasalapplication forms. Preparations for oral or rectal administrationinclude for example, capsules, tablets, pills, powders, cashes,suppositories, solutions, etc. Injections include for example,sterilized solutions or emulsions, etc. Topical administrationpreparations include, for example creams, ointments, lotions,transdermal preparations (usual paches, matrixs), etc.

The above preparations are prepared with pharmaceutically acceptablefillers and additives by the conventional method. Pharmaceuticallyacceptable fillers and additives include carriers, binders, flavors,buffering agents, viscosity-increasing agents, coloring agents,stabilizing agents, emulsifiers, dispersing agents, suspending agents,preservatives, etc.

Pharmaceutically acceptable carriers include, for example magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, wax (lower melting point), cacao butter, etc. Capsules can beprepared by putting the compound of the present invention withpharmaceutically acceptable carriers. The compound of the presentinvention is mixed with pharmaceutically acceptable fillers and themixture is put into capsules, or the compound without any filler is putinto capsules. Caches can be prepared by the same method as thecapsules.

Solutions for injection include, for example solutions, suspensions,emulsions, etc. such as an aqueous solution, water-propylene glycolsolution. The solution may contain water and can be prepared inpropylene glycol or/and propylene glycol solution. The solutionssuitable for oral administration can be prepared by adding the compoundof the present invention into water and if necessary, adding a coloringagent, a flavor, a stabilizing agent, a sweetening, a solubilizingagent, a viscosity-increasing agent, etc. Also the solutions suitablefor oral administration can be prepared can be prepared by adding thecompound of the present invention and a dispersing agent into water tomake viscositic solutions. The viscosity-increasing agents include, forexample natural or synthetic gum, resin, methylcellulose, sodiumcarboxymethyl cellulose, or known emulsifiers.

The preparations for topical administration include for example abovementioned solutions, creams, aerosols, sprays, powders, lotions,ointments, etc. The preparations for topical administration can beprepared by mixing the compound of the present invention,pharmaceutically acceptable diluents and carriers conventionally used.Creams and ointments can be prepared, for example by mixing aqueous oroil bases and viscosity-increasing agents and/or gelating agents. Thebases include, for example water, liquid paraffin, plant oil (peanutoil, castor oil), etc. The viscosity-increasing agents include, forexample soft paraffin, aluminum stearate, cetostearyl alcohol, propyleneglycol, polyethylene glycol, lanolin, hydrogenated lanolin, bees wax,etc. The lotions can be prepared by mixing aqueous or oil bases, and oneor more pharmaceutically acceptable stabilizing agents, suspendingagents, emulsifiers, dispersing agents, viscosity-increasing agents,coloring agents, flavors, etc.

The powders are prepared with pharmaceutically acceptable powder bases.The bases are talc, lactose, starch, etc. Drops can be prepared withaqueous or non-aqueous bases and one or more pharmaceutically acceptabledispersing agents, suspending agents, solbilizing agents, etc.

The preparations for topical administration may contain, if necessarypreservatives, such as hydroxy benzoic acid methyl ester, hydroxybenzoic acid propyl ester, chloro cresol, benzalkonium chloride, andantibacterial agents.

Liquids for spray, powders or drops containing the compound of thepresent invention can be nasally administered.

Dose and number of administration vary with a disease to be treated,age, body weight, route of administration. In case of oraladministration, an active ingredient is administered to an adultgenerally about 1-500 mg per day, preferably about 5-100 mg, once orseveral times. In case of injections, an active ingredient isadministered generally about 0.1-300 mg per day, preferably about 1-100mg, once or several times.

EXAMPLE

The present invention is in more detail explained by examples,reference-examples and tests, but the present invention should not belimited to them.

Example 1Ethyl-2-[(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)amino]acetate

To a mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (100mg, 0.545 mmol), triethylamine (221 mg, 2.18 mmol) and butanol (3 ml)was added glycine ethyl ester hydrochloride (152 mg, 100 mmol) at roomtemperature. After the mixture was stirred for 4 hours at 90° C., thereaction mixture was poured into water and extracted with chloroform.The organic layer was washed with saturated brine, dried over sodiumsulfate, filtered and the solvent in the filtrate was removed in vacuo.The residue was purified by silica gel chromatography (3% MeOH/CHCl₃) togive the object compound (98.3 mg, 72.1%).

¹H-NMR (CDCl₃): δ 1.30 (3H, t, J=7.0 OHz), 1.78 (4H, m), 2.30 (2H, m),2.55 (2H, m), 4.20 (2H, m), 4.24 (2H, q, J=7.0 Hz), 4.76 (2H, bs), 5.13(1H, bs).

Example 2N-(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)-N-(cyclohexylmethyl)amine

A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (107 mg,0.58 mmol), triethylamine (221 mg, 2.18 mmol), cyclohexylmethylamine(132 mg, 1.17 mmol) and n-butanol (3 ml) was reacted for 4 hours at80-90° C. According to the post-treatment of Example 1, the objectcompound was obtained (102 mg, 67.9%).

¹H-NMR (CDCl₃): δ 0.97 (2H, m), 1.22 (3H, m), 1.56 (1H, m), 1.76 (9H,m), 2.21 (2H, m), 2.55 (2H, m), 3.28 (2H, t, J=6.8 Hz), 4.71 (1H, bt),5.03 (2H, bs).

Example 3Ethyl-2-[(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)amino]-4-methylpentanoate

A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (117 mg,0.64 mmol), triethylamine (259 mg, 2.56 mmol), dl-leucine ethyl esterhydrochloride (250 mg, 1.28 mmol) and n-butanol (2 ml) was reacted for 6hours at 80-90° C. According to the post-treatment of Example 1, theobject compound was obtained (104.3 mg, 72.1%).

¹H-NMR (CDCl₃): δ 0.92 (6H, m), 1.30 (3H, t, J=7.1 Hz), 1.60-1.70 (3H,m), 1.79 (4H, m), 2.29 (2H, m), 2.54 (2H, m), 4.18 (2H, q, J=7.1 Hz),4.80 (1H, m), 4.88 (2H, bs), 4.90 (1H,bs).

Example 4N-(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)-N-(2-ethoxyethyl)amine

To a mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (100mg, 0.545 mmol), triethylamine (221 mg, 2.18 mmol) and dimethylformamide(2 ml) was added ethoxyethylamine (98 mg, 1.10 mmol) at roomtemperature. After the mixture was stirred for 2.5 hours at 90° C., thereaction mixture was poured into water and extracted with chloroform.The organic layer was washed with saturated brine, dried over sodiumsulfate, filtered and the solvent in the filtrate was removed in vacuo.The residue was purified by preparative TLC (10% MeOH/CHCl₃) to give theobject compound (41.7 mg, 32.4%).

¹H-NMR (CDCl₃): δ 1.22 (3H, t, J=6.8 Hz), 1.80 (4H, m), 2.23 (2H, m),2.59 (2H, m), 3.53 (2H, q, J=6.8 Hz), 3.62 (4H, m), 5.17 (1H, bt), 5.30(2H, bs).

Example 5 N-(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)-N-butylamine

A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (100 mg,0.545 mmol) and butylamine (2 ml) was stirred for 4 hours at 90° C. Thereaction mixture was poured into water and extracted with chloroform.The organic layer was washed with saturated brine, dried over sodiumsulfate, filtered and the solvent in the filtrate was removed in vacuo.The residue was purified by column chromatography (10% MeOH/CHCl₃) togive the object compound (94.5 mg, 78.9%).

¹H-NMR (CDCl₃): δ 5 0.93 (3H, t, J=7.0 Hz), 1.36 (2H, m), 1.63 (2H, m),1.78 (4H, m), 2.31 (2H, m), 2.58 (2H, m), 3.47 (2H, q, J=7.0 Hz), 6.00(1H, bs), 6.03 (1H, t like), 7.34(1H, bs).

Example 6 N-(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)-N-hexylamine

According to the method of Example 5, the above compound was obtained.

¹H-NMR (CDCl₃): δ 0.89 (3H, m), 1.32 (6H, m), 1.59 (2H, m), 1.81 (4H,m), 2.21 (2H, m), 2.62 (2H, m), 3.44 (2H, q, J=7.0 Hz), 4.99 (lH, bs),5.73 (2H, brs).

Example 7 Ethyl2-[(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)amino]propanoate

To a mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (100mg, 0.545 mmol), triethylamine (221 mg, 2.18 mmol) and dimethylformamide(4 ml) was added 2-aminopropionic acid ethyl ester hydrochloride (167mg, 1.09 mmol) at room temperature. After the mixture was stirred for2.5 hours at 100° C., the reaction mixture was poured into water andextracted with chloroform. The organic layer was washed with saturatedbrine, dried over sodium sulfate, filtered and the solvent in thefiltrate was removed in vacuo. The residue was purified by silica gelchromatography (5% MeOH/CHCl₃) to give the object compound (42.1 mg,29.3%).

¹H-NMR (300 MHz, CDCl₃): δ 5.07 (brd, 1H, J=6.8 Hz), 4.79-4.69 (3H, m),4.21 (q, 2H, J=7.1 Hz), 2.56-2.53 (2H, m), 2.32-2.25 (2H, m), 1.85-1.73(4H, m), 1.47 (d, 3H, J=7.1 Hz), 1.29 (t, 3H, J=7.1 Hz).

Example 8 Ethyl2-[(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)amino]-3-hydroxypropanoate

According to the method of Example 7, the above compound was obtained.

1H-NMR (300 MHz, CDCl₃): δ 5 5.63 (d, 1H, J=6.2 Hz), 4.84-4.76 (3H, m),4.26-4.20 (2H, m), 4.08 (dd, 1H, J=11.0, 3.1 Hz), 3.94 (dd, 1H, J=11.0,1.9 Hz), 2.55-2.47 (2H, m), 2.32-2.25 (2H, m), 1.80-1.70 (4H, m), 1.31(t, 3H, J=7.1 Hz).

Example 9 Methyl2-[(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)amino]hexanoate

According to the method of Example 7, the above compound was obtained.

¹H-NMR (300 MHz, CDCl₃): δ 4.94 (d, 1H, J=7.7 Hz), 4.85-4.75 (1H, m),4.74 (1H, brs), 3.74 (3H, s), 2.57-2.50 (2H, m), 2.30-2.50 (2H, m),1.95-1.65 (6H, m), 1.40-1.25 (4H, m), 0.92-0.87 (3H, m).

Example 102-[(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)amino]hexane-1-ol

Methyl 2-[(2-amino-5,6,7,8-tetrahydroquinazoline-2-ylamino]hexanoate(122 mg, 0.417 mmol) was dissolved in THF (3 ml). To the solution wasadded lithium aluminum hydride (15 mg, 0.417 mmol) at 0° C. and it waswarmed to room temperature. The reaction mixture was cooled and THF (10ml) was dropped thereto, followed by dropping water (1 ml). Then 1M NaOHaqueous solution was added until the solid developed. MgSO₄ was added tothe reaction mixture and the mixture was filtered. To the filtrate wereadded a saturated aqueous sodium hydrogen carbonate solution andchloroform and it was extracted. The organic layer was washed withsaturated brine, dried over sodium sulfate, filtered and the solvent inthe filtrate was removed in vacuo. The residue was purified bypreparative TLC (15% MeOH/CHCl₃) to give the object compound (27 mg,24.5%).

¹H-NMR (300 MHz, CDCl₃): δ 5.46 (brs, 1H), 4.97 (d, 1H, J=7.1 Hz), 4.50(2H, brs), 4.20-4.10 (1H, m), 3.76 (dd, 1H, J=11.0, 3.1 Hz), 3.62 (dd,1H, J=11.0, 6.6 Hz), 2.60-2.50 (2H, m), 2.35-2.15 (2H, m), 1.85-1.70(4H, m), 1.70-1.45 (2H, m), 1.40-1.35 (4H, m), 0.93-0.88 (3H, m).

Example 111-[(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)amino]pentane-2-ol

A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (184 mg, 1mmol), 2-hydroxypentylamine hydrochloride (140 mg, 1 mmol),triethylamine (202 mg, 2 mmol) and DMF (1 ml) was warmed for 5 hours ina bath (bath temperature, 90° C.). The solvent in the filtrate wasremoved in vacuo and the residue was purified by silica gel columnchromatography (CHCl₃:MeOH:NH₄OHaq=100:10:0.4) to give the crude product(210 mg). To the crude product was aqueous ammonia solution (5 ml) andchloroform (30 ml) and it was extracted. The organic layer was washedwith saturated brine (20 ml), dried over sodium sulfate, filtered andthe solvent in the filtrate was removed in vacuo to give the objectcompound (128 mg, 51%).

¹H-NMR (300 MHz, CDCl₃): δ 4.93 (1H, brm), 4.62 (2H, brs), 3.75-3.85(1H, m), 3.55-3.65 (1H, m), 3.33-3.44 (1H, m), 2.50-2.54 (2H, m),2.20-2.22 (2H, m), 1.77-1.79 (4H, m), 1.38-1.54 (4H, m), 0.95 (3H, t,J=7.3 Hz).

Example 121-[(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)amino]pentane-2-one

To a solution of1-[2-amino-5,6,7,8-tetrahydroquinazoline-4-yl)amino]pentane-2-ol (120mg, 0.479 mmol) in dichloromethane (20 ml) was added pyridiniumchlorochromate (517 mg, 23.97 mmol) and the mixture was stirred for 3.5hours. Silica gel (10 g) was added to the reaction mixture and it wasfiltered. The silica gel was washed with 5% MeOH/CHCl₃. The filtrateswere collected and the solvent was removed in vacuo. The residue waspurified by silica gel chromatography (CHCl₃:MeOH:NH₄OHaq=100:5:0.4) togive the object compound (32 mg, 26%).

¹H-NMR (300 MHz, CDCl₃): δ 5.36 (1H, brs), 4.62 (2H, brs), 4.28 (2H, d,J=4.0 Hz), 2.46-2.57 (4H, m), 2.30-2.32 (2H, m), 2.02 (1H, brm),1.65-1.81 (6H, m), 0.96 (3H, t, J=7.3 Hz).

Example 13N-(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)-N-(tetrahydorofuran-2-ylmethyl) amine

A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (184 mg, 1mmol), tetrahydrofurfurylamine (101 mg, 1 mmol) and diethyleneglycoldiethyl ether (1 ml) was kept to warm for 2 hours at 100-110° C. Thereaction mixture was extracted with ethyl acetate (50 ml) and asaturated aqueous sodium hydrogen carbonate (20 ml). The organic layerwas washed with saturated brine, dried over sodium sulfate, filtered andthe solvent in the filtrate was removed in vacuo. The residue waspurified by column chromatography (CHCl₃:MeOH:NH₄OHaq=100:10:0.4) togive the object compound (80 mg, 32.3%).

¹H-NMR (300 MHz, CDCl₃): δ 5 4.98 (1H, brs), 4.87 (1H, brs), 4.01-4.11(1H, m), 3.71-3.92 (3H, m), 3.29-3.38 (1H, m), 3.14 (1H, brm), 2.54-2.58(2H, m), 2.22-2.24 (2H, m), 1.77-2.07 (8H, m).

Example 14 N-(2-Amino-5-butyl-6-methylpyrimidine-4-yl)-N-pentylamine

A mixture of 5-butyl-4-chloro-6-methylpyrimidine-2-yl amine (100 mg, 0.5mmol) and amylamine (2 ml) was refluxed for 11 hours. The reactionmixture was cooled and the solvent was removed in vacuo and the residuewas purified by silica gel column chromatography (MeOH:CHCl₃=1:20) togive the object compound (98 mg, 78%) as an oil.

¹H-NMR (CDCl₃): δ 0.93 (6H, m), 1.37 (8H, brm), 1.60 (2H, m), 2.30 (3H,s), 2.32 (2H, m), 3.44 (2H, q-like), 4.96 (1H, br), 5.59 (2H, br).

Example 15 N-(2-Amino-5-hexyl-6-methylpyrimidine-4-yl)-N-pentylamine

A mixture of 4-chloro-5-hexyl-6-methylpyrimidine-2-ylamine (1.00 mg,0.44 mmol) and amylamine (2 ml) was refluxed for 11 hours. The reactionmixture was cooled and the solvent was removed in vacuo. The residue waspurified by silica gel column chromatography (MeOH:CHCl₃=1:20) to givethe object compound (107 mg, 87%) as an oil.

¹H-NMR (TMS/CDCl₃): δ 0.91 (6H, m), 1.36 (12H, brm), 1.60 (2H, m), 2.29(3H, s), 2.31 (2H, m), 3.43 (2H, q-like), 4.90 (1H, br), 5.50 (2H, br)

Example 16N-(2-Amino-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-4-yl)-N-pentylamine

A mixture of 4-chloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2-ylamine(29.3 mg, 0.158 mmol) and amylamine (1.0 ml) was refluxed for 2.5 hours.After reaction, the procedure according to pro-treatment of Example 7was carried out to give the object compound (22.3 mg, 59%).

¹H-NMR (300 MHz, CDCl₃): δ 4.86 (2H, brs), 4.40 (2H, d, J=1.1 Hz), 4.09(1H, brs), 3.94 (2H, t, J=5.6 Hz), 3.41 (2H, dt, J=7.1,5.4 Hz), 2.64(2H, t, J=5.6 Hz), 1.64-1.50 (2H, m), 1.42-1.25 (4H, m), 0.96-0.86 (3H,m).

EXAMPLE 17 N-(2-Amino-6-butyl-5-methylpyrimidine-4-yl)-N-pentylamine

A mixture of 4-butyl-6-chloro-5-methylpyrimidine-2-ylamine (93.5 mg,0.47 mmol) and amylamine (1.5 ml) was refluxed for 8 hours. Afterreaction, the procedure according to pro-treatment of Example 7 wascarried out to give the object compound (50 mg, 42.7%).

¹H-NMR (CDCl₃): δ 0. 93 (6H, tx2), 1.37 (6H, m), 1.57 (4H, m), 1.91 (3H,s), 2.51 (2H, t, J=7.6 Hz), 3.40 (2H, q, J=7.3 Hz), 4.61 (1H, bs), 4.98(2H, bs).

Example 18 N-(2-Amino-5,6-dimethylpyrimidine-4-yl)-N-pentylamine

A mixture of N-(2-chloro-5,6-dimethylpyrimidine-4-yl)-N-pentylamine (131mg, 0.575 mmol) and 5M ammonia-ethanol (40 ml) was kept at 170° C. for10 hours. The reaction mixture was concentrated in vacuo, purified bypreparative TLC (20%MeOH/CHCl₃) to give the object compound (4.2 mg,3.5%).

¹H-NMR (300 MHz, CDCl₃): δ 5.17 (2H, brs), 4.56 (1H, brs), 3.82-3.45(2H, m), 2.25 (3H, s), 1.90 (3H, s), 1.65-1.55 (2H, m), 1.37-1.32 (4H,m), 0.94-0.89 (3H, m).

Example 19 N-(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)-N-pentylamine

By using N-(2-chloro-5,6,7,8-tetrahydroquinazoline-4-yl)-N-pentylamineas a starting material and according to the method of Example 18, theobject compound was obtained.

¹H-NMR (300 MHz, CDCl₃): δ 5.11 (2H, brs), 4.52 (1H, brs), 3.86-3.52(2H, m), 2.57-2.54 (2H, m), 2.21-2.18 (2H, m), 1.83-1.75 (4H, m),1.64-1.74 (2H, m), 1.40-1.30 (4H, m), 0.94-0.89 (3H, m).

Example 20N-(2-Amino-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-N-pentylamine

By using2-chloro-N-pentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine as astarting material and according to the method of Example 18, the objectcompound was obtained.

¹H-NMR (300 MHz, CDCl₃): δ 4.89 (2H, brs), 4.31 (1H, brs), 3.46-3.88(2H, m), 2.75 (2H, t, J=7.7 Hz), 2.55 (2H, t, J=7.7 Hz), 2.07 (2H, tt,J=7.7,7.7 Hz), 1.64-1.54 (2H, m), 1.37-1.32 (4H, m), 0.94-0.89 (3H, m).

Example 212-(2-Amino-5,6,7,8-tetrahydroquinazoline-4-yl)amino]hexaneamide

A mixture of methyl2-[(2-amino-5,6,7,8-tetrahydroquinazoline-4-yl)amino]hexanoate (520 mg,1.77 mmol) and 5M ammonia-ethanol (60 ml) was kept at 120° C. for 24hours. The reaction mixture was concentrated in vacuo, purified bysilica gel chromatography (20%MeOH/CHCl₃) to give the object compound(67.7 mg, 7.6%).

¹H-NMR (300 MHz, DMSO-d₆): δ 7.26 (1H, brs), 7.01 (1H, brs), 5.80 (1H,d, J=7.9 Hz), 5.58 (2H, brs), 4.46 (1H, dt, J=8.1, 7.9 Hz), 2.43-2.21(4H, m), 1.85-1.56 (6H, m), 1.34-1.13 (4H, m), 0.92-0.77 (3H, m).

Example 22N-(2-Amino-5-(2-methoxyethyl)-6-methylpyrimidine-4-yl)-N-pentylamine

A mixture of 4-chloro-5-(2-methoxyethyl)-6-methylpyrimidine-2-ylamine(150 mg, 0.74 mmol), amylamine (0.86 ml) and dioxane (1.5 ml) was keptat 90° C. for 7 hours. The reaction mixture was concentrated in vacuo,and the residue was extracted with chloroform and a saturated aqueousNaHCO₃ solution. The organic layer was washed with saturated brine,dried over sodium sulfate, filtered and the filtrate was concentrated invacuo. The residue was purified by column chromatography (4%MeOH: CHCl₃)to give the object compound (108 mg, 57.5%).

¹H-NMR (CDCl₃): δ 0.92 (3H, t, J=6.6), 1.40-1.32 (4H, m), 1.57 (2H, m),2.21 (3H, s), 2.62 (2H, t, J=5.9), 3.31-3.38 (5H, m), 3.50 (2H, t,J=5.9), 4.72 (2H, brs), 5.62 (1H, m).

Example 233-[2-Amino-4-methyl-6-(pentylamino)pyrimidine-5-yl]propanenitrile

A mixture of 3-(2-amino-4-chloro-6-methylpyrimidine-5-yl)propanenitrile(500 mg, 2.54 mmol), amylamine (2.94 ml) and dioxane (5 ml) was kept at90° C. for 8.5 hours. The procedure according to pro-treatment ofExample 23 was carried out to give the object compound (346 mg, 55.0%).

¹H-NMR (CDCl₃): δ 0.92 (3H, t, J=6.9), 1.35 (4H, m), 1.60 (2H, m), 2.25(3H, s), 2.45 (2H, t, J=7.9), 2.75 (2H, t, J=7.9), 3.40 (2H, m), 4.45(1H, m), 4.65 (2H, brs).

Example 24 N-[2-Amino-5-ethyl-6-methylpyrimidine-4-yl)-N-pentylamine

A mixture of 4-chloro-5-ethyl-6-methylpyrimidine-2-ylamine (400 mg,33mmol), amylamine (1.35 ml) and dioxane (5 ml) was kept at 95-100° C. for17 hours. The procedure according to pro-treatment of Example 23 wascarried out to give the object compound (301 mg, 58.1%).

¹H-NMR (CDCl₃): δ 0.91 (3H, t, J=6.9), 1.06 (3H, t, J=7.6), 1.23-1.43(4H, m), 1.59 (2H, m), 2.22 (3H, s), 2.35 (2H, q, J=7.6), 3.40 (2H, m),4.50 (1H, m), 4.61 (2H, brs).

Example 25

According to the method of Example 23, the following compound wasobtained:

1-[(2-Amino-5-butyl-6-methylpyrimidine-4-yl)amino]pentane-2-ol

¹H-NMR (CDCl₃): δ 0.94 (6H, t), 1.45 (8H, m), 2.34 (3H, s), 2.37 (2H,m), 3.31 (1H, m), 3.48 (1H, s), 3.76 (2H, m), 6.10 (1H, brs), 6.32 (2H,brs).

Example 26 N-(2-Amino-5-benzyl-6-methylpyrimidine-4-yl)-N-pentylamine

A mixture of 5-benzyl-4-chloro-6-methylpyrimidine-2-ylamine (500 mg,2.14 mmol) , amylamine (1.24 ml ) and dioxane (4 ml ) was kept at95-100° C. for 19 hours. The reaction mixture was concentrated in vacuo,and the residue was extracted with chloroform and a saturated aqueousNaHCO₃ solution. The organic layer was washed with saturated brine,dried over sodium sulfate, and concentrated in vacuo. The residue waspurified by silica gel column chromatography (2%MeOH/CHCl₃) to give theobject compound (546 mg, 89.7%).

¹H-NMR (CDCl₃): δ 0.81 (3H, t, J=7.3), 1.05 (2H, m), 1.19 (2H, m), 1.35(2H, m), 2.28 (3H, s), 3.27 (2H, m), 3.76 (2H, s), 4.30 (1H, m), 4.64(2H, brs), 7.12-7.31 (5H, m), 0.94-0.89 (3H, m).

Example 27 N-(2-Amino-5-benzylpyrimidine-4-yl)-N-pentylamine

A mixture of 5-benzyl-4-chloropyrimidine-2-ylamine (350 mg, 0.74 mmol),amylamine (0.74 ml) and dioxane (4 ml) was kept at 90-100° C. for 8hours. The reaction mixture was concentrated in vacuo, and the residuewas extracted with ether and a saturated aqueous NaHCO₃ solution. Theorganic layer was washed with saturated brine, dried over sodiumsulfate, filtered and concentrated. The residue was purified by silicagel column chromatography (MeOH:CHCl₃=70:1) to give the object compound(355 mg, 82.2%).

¹H-NMR (CDCl₃): δ 0.82 (3H, t, J=6.9), 1.04 (2H, m), 1.21 (2H, m), 1.35(2H, m), 3.26 (2H, m), 3.66 (2H, s), 4.26 (1H, m), 4.64 (2H, brs),7.16-7.33 (5H, m), 7.68 (1H, s).

Example 28 N-(2-Amino-5-phenethylpyrimidine-4-yl)-N-pentylamine

A mixture of 4-chloro-5-phenethylpyrimidine-2-ylamine (234 mg, 1 mmol),amylamine (0.58 ml) and dioxane (2 ml) was kept at 95-100° C. for 8.5hours. The procedure according to pro-treatment of Example 27 wascarried out to give the object compound (227 mg, 79.7%).

¹H-NMR (CDCl₃): δ 0.91 (3H, t, J=6.9), 1.25-1.42 (4H, m), 1.50 (2H, m),2.55 (2H, t, J=7.3), 2.84 (2H, t, J=7.3), 3.31 (2H, m), 4.27 (1H, m),4.60 (2H, brs), 7.15-7.33 (5H, m), 7.56 (1H, s).

Example 29 N-(2-Amino-5-benzyl-6-methylpyrimidine-4-yl)-N-pentane-2-ol

A mixture of 5-benzyl-4-chloro-6-methylpyrimidine-2-yl amine (1.5 g,6.42 mmol), 2-hydroxypentylamine hydrochloride (990 mg, 7.06 mmol),triethylamine (1.4 g, 14.18 mmol) and diethyleneglycol diethyl ether (5ml) was kept to warm for 15 hours in a bath (bath temperature: 90-100°C.). The solvent was removed in vacuo and the residue was purified bysilica gel column chromatography (CHCl₃:MeOH:NH₄OHaq=100:10:0.4) to givethe object compound (800 mg, 41.5%).

¹H-NMR (TMS/CDCl₃): d 0.86 (3H, t, J=6.9 Hz), 1.18-1.40 (4H, m), 2.27(3H, s), 3.17-3.27 (1H, m), 3.60-3.71 (1H, m), 3.78 (2H, d, J=6.6 Hz),4.76 (3H, br), 7.23 (2H, d, J=6.9 Hz), 7.28-7.33 (3H, m).

Example 30

The compounds in the following table can be prepared according to themethods of the above Examples.

No. R1 R2 R3 1

—Me —(CH₂)₃Me 2

—Me

3

—Me —CH₂CH₂CN 4

—Me —CH₂CH₂CONH₂ 5

—Me

6

—Me

7

—(CH₂)₄— 8 —(CH₂)₄Me —Me —CH₂CH₂NHSO₃Me 9 —(CH₂)₄Me —Me

10 —(CH₂)₄Me —Me —(CH₂)₃NH₂ 11 —(CH₂)₄Me —Me —CH₂CH₂CONH₂ 12 —(CH₂)₄Me—Me

13 —(CH₂)₄Me —Et

14 —(CH₂)₄Me —(CH₂)₃— 15

—Me —(CH₂)₃Me 16

—Me

17

—Me —CH₂CH₂CN 18

—Me —CH₂CH₂CONH₂ 19

—Me

20

—Me

21

—(CH₂)₃— 22

—Me —(CH₂)₃Me 23

—Me

24

—Me —CH₂CH₂CN 25

—Me —CH₂CH₂CONH₂ 26

—Me

27

—(CH₂)₄—

Reference Example 1 4-Chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine

(1-1) 2-Amino-5,6,7,8-tetrahydroquinazoline-4-ol

To a solution of ethyl 2-oxocyclohexane carboxylate (41 g, 241 mmol) inethanol (200 ml) was added guanidine carbonate (26.0 g, 289 mmol) understirring at room temperature. The reaction mixture was refluxed for 1hour and then cooled to room temperature. The precipitated crystals werefiltered and washed with water, followed with methanol. The crystalswere dried in vacuo to give the object compound (35.5 g, 89%).

¹H-NMR (300 MHz, DMSO-d₆): δ 10.64 (1H, brs), 6.18 (2H, brs), 2.35-2.25(2H, m), 2.23-2.15 (2H, m), 1.70-1.54 (4H, m).

(1-2) 4-Chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine

To a suspension of 2-amino-5,6,7,8-tetrahydroquinazoline-4-ol (20.0 g,121 mmol) in toluene (150 ml) was dropped phosphorus oxychloride (55.7g, 363 mmol) at 90° C. The mixture was stirred for 1 hour and thesolvent was removed in vacuo. The residue was poured into 28% aqueousammonia solution at 0° C. The solid was filtered and purified by silicagel column chromatography (3%MeOH/CHCl₃) to give the object compound(13.5 g, 60%).

¹H-NMR (300 MHz, DMSO-d₆): δ 6.69 (2H, brs), 2.60-2.52 (2H, m),2.52-2.44 (2H, m), 1.76-1.66 (4H, m).

¹³C NMR (75 Hz, DMSO-d₆): δ 168.4, 161.0, 160.1, 114.8, 31.8, 24.3,22.1, 21.7.

Reference Example 2 5-Butyl-4-chloro-6-methylpyrimidine-2-ylamine

(2-1) 2-Amino-5-butyl-6-methylpyrimidine-4-ol

A mixture of ethyl 2-acetylhexanoate (5.59 g, 30 mmol), guanidinecarbonate (6.49 g, 30 mmol) and ethanol (20 ml) was refluxed for 11hours and then ice-cooled. The precipitated crystals were filtered,washed with ethanol and dried in vacuo to give2-amino-5-butyl-6-methylpyrimidine-4-ol (2.59 g, 47%).

(2-2) 5-Butyl-4-chloro-6-methylpyrimidine-2-ylamine

2-Amino-5-butyl-6-methylpyrimidine-4-ol (1.0 g, 5.52 mmol) andphosphorus oxychloride (12 ml) were refluxed for 3 hours. The solventwas removed in vacuo and the residue was purified by silica gel columnchromatography(n-hexane: ethyl acetate=2:1) to give the object compound(325 mg, 29%).

¹H-NMR(CDCl₃): δ 0.96 (3H, t, J=7.1 Hz), 1.37-1.50 (4H, m), 2.38 (3H,s), 2.60 (2H, m), 5.01 (2H, brs).

Reference-Example 3 4-Chloro-5-hexyl-6-methylpyrimidine-2-ylamine

By using ethyl 2-acetyloctanoate (6.43 g, 30 mmol) as a startingmaterial and according to the method of Reference-example 2, there wasobtained 2-amino-5-hexyl-6-methylpyrimidine-4-ol (4.70 g, 74%). Byreacting the obtained 2-amino-5-hexyl-6-methylpyrimidine-4-ol (1 g, 4.78mmol) and phosphorous oxychloride (12 ml), there was obtained the objectcompound (196 mg, 18%).

¹H-NMR(CDCl₃): δ 0.90 (3H, t, J=6.8 Hz), 1.31-1.52 (8H, m), 2.37 (3H,s), 2.59 (2H, m), 4.95 (2H, brs).

Reference-Example 44-Chloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2-ylamine

(4-1) 2-Amino-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-4-ol

By using ethyl 4-oxotetrahydoro-2H-pyran-3-carboxylate (600 mg, 3.49mmol) as a starting material and according to the method ofReference-example 2, there was obtained2-amino-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-4-ol (230 mg, 39%).

¹H-NMR (300 MHz, DMSO-d₆): δ 10.78 (1H, brs), 6.34 (2H, brs), 4.24 (2H,brs), 3.78 (2H, t, J=5.5 Hz), 2.36 (2H, t).

(4-2) 4-Chloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2-ylamine

By reacting 2-amino-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-4-ol (562 mg,3.36 mmol) and phosphorous oxychloride (3 ml), there was obtained theobject compound (136 mg, 22%).

¹H-NMR (300 MHz, CDCl₃): δ 5.10 (1H, brs), 4.62 (2H, s), 3.99 (2H, t,J=5.4 Hz), 2.78 (2H, t, J=5.4 Hz).

Reference-Example 5 4-Butyl-6-chloro-5-methylpyrimidine-2-ylamine

(5-1) 2-Amino-6-butyl-5-methylpyrimidine-4-ol

By using ethyl 2-methyl-3-oxoheptanoate (1.06 g, 5.69 mmol) as astarting material and according to the method of Reference-example 2,there was obtained 2-amino-6-butyl-5-methylpyrimidine-4-ol (420 mg).

¹H-NMR (DMSO-d₆): δ 0.88 (3H, t, J=7.3 Hz), 1.30 (2H, m), 1.49 (2H, m),1.78 (3H, s), 2.32 (2H, t, J=7.3 Hz), 6.18 (2H, bs), 10.69 (1H, bs).

(5-2) 4-Butyl-6-chloro-5-methylpyrimidine-2-ylamine

By reacting 2-amino-6-butyl-5-methylpyrimidine-4-ol (0.82 g, 4.52 mmol)and phosphorous oxychloride (10 ml), there was obtained the objectcompound (720 mg).

¹H-NMR (CDCl₃): δ 0.93 (3H, t, J=7.3 Hz), 1.40 (2H, m), 1.60 (2H, m),2.20 (3H, s), 2.63 (2H, t, J=7.3 Hz), 5.73 (2H, bs).

Reference-Example 64-Chloro-5-(2-methoxyethyl)-6-methlpyrimidine-2-ylamine

(6-1) 2-Amino-5-(2-methoxyethyl)-6-methlpyrimidine-4-ol

A mixture of ethyl 2-(2-methoxyethyl)-3-oxobutanoate (4 g, 21 mmol),guanidine carbonate (2.27 g, 16.3 mmol) and ethanol (16 ml) was refluxedfor 9 hours. After cooling, the precipitate was filtered and washed withwater, ethanol and ether in order, to give the object compound (1.24 g,31.9%)

¹H-NMR (DMSO-d₆): δ 2.06 (3H, s), 2.49-2.54 (4H(2H),m, overlapped withDMSO), 3.22 (3H, s), 3.28 (2H, t, J=7.3), 6.40 (2H, brs), l0.90 (1H,brs).

(6-2) 4-Chloro-5-(2-methoxyethyl)-6-methylpyrimidine-2-ylamine

A mixture of 2-amino-5-(2-methoxyethyl)-6-methylpyrimidine-4-ol (600 mg,3.27 mmol) and phosphorus oxychloride (6 ml) was kept at 90° C. for 5.5hours. The reaction mixture was concentrated in vacuo. Was added to theresidue and an aqueous ammonia solution was cautiously added. Themixture was extracted with chloroform and the organic layer was washedwith saturated brine, dried over sodium sulfate and the solvent wasconcentrated. The residue was purified by silica gel columnchromatography (chloroform: ethyl acetate=8:2) to give the objectcompound (200 mg, 30.3%).

¹H-NMR(CDCl₃): δ 2.42 (3H, s), 2.91 (2H, t, J=7.3), 3.34 (3H, s), 3.51(2H, t, J=7.3), 5.03 (2H, brs).

Reference-Example 73-(2-Amino-4-chloro-6-methlpyrimidine-5-yl)propanenitrile

(7-1) 3-(2-Amino-4-hydroxy-6-methlpyrimidine-5-yl)propanenitrile

A mixture of ethyl 2-(2-cyanoethyl)-3-oxobutanoate (9 g, 49 mmol),guanidine carbonate (5.30 g, 29.4 mmol) and pyridine (49 ml) was kept at100° C. for 8 hours. The procedure according to pro-treatment ofReference-example 6 was carried out to give the object compound (3.38 g,38.6%).

¹H-NMR (DMSO-d₆): δ 2.11 (3H, s), 2.58 (4H, s), 6.44 (2H, brs), 10.91(1H, brs).

(7-2) 3-(2-Amino-4-chloro-6-methlpyrimidine-5-yl)propanenitrile

A mixture of 3-(2-amino-4-hydroxy-6-methylpyrimidine-5-yl)propanenitrile(2 g, 11.2 mmol) and phosphorous oxychloride (13 ml) was kept at 90° C.for 5 hours. The procedure according to pro-treatment ofReference-example 6 was carried out to give the object compound (1.06 g,48%).

¹H-NMR (CDCl₃): δ 2.47 (3H, s), 2.61 (2H, t, J=7.6), 3.02 (2H, t,J=7.6), 5.11 (2H, brs).

Reference-Example 8 4-Bromo-5,6,7,8-tetrahydroquinazoline-2-ylamine

To a suspension of 2-amino-5,6,7,8-tetrahydroquinazoline-4-ol (1.65 g,10 mmol) in toluene (16.5 ml) was added phosphorous oxybromide (3 g) andthe mixture was kept to warm in a bath (bath temperature 90-100° C.) for2 hours. After confirming disappearance of the starting materials, thereaction mixture was poured into ice-water, and was extracted withchloroform and a saturated aqueous NaHCO₃ solution. The organic layerwas washed with saturated brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (CHCl₃) to give the object compound (1.7 g, 75%).

¹H-NMR (300 MHz, CDCl₃): δ 5.13 (2H, brs), 2.66 (2H, brm), 2.57 (2H,brm), 1.77-1.82 (4H, m).

Reference-Example 9 2-Chloro-N-pentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

(9-1) 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]-pyrimidine

6,7-Dihydro-5H-cyclopenta [d]pyrimidine-2,4-diol (359 mg) andphosphorous oxychloride (5 ml) were refluxed for 3 hours. After thereaction, the mixture was concentrated in vacuo. The residue was pouredinto water and extracted with chloroform. The organic layer was washedwith saturated brine, dried over sodium sulfate and concentrated invacuo to give 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (410mg).

(9-2) 2-Chloro-N-pentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine

A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (410mg) and pentylamine (1 ml) were stirred at room temperature for 8 hours.The reaction mixture was poured into an aqueous ammonium chloridesolution and the solution was extracted with chloroform. The organiclayer was washed with saturated brine, dried over sodium sulfate andconcentrated in vacuo to give the object compound (296 mg, 65%).

¹H-NMR (300 MHz, CDCl₃): δ 4.56 (1H, brs), 3.52-3.46 (2H, m), 2.86 (2H,t, J=7.5 Hz), 2.63 (2H, t, J=7.5 Hz), 2.13 (2H, tt, J=7.5,7.5 Hz),1.66-1.57 (2H, m), 1.40-1.33 (4H, m), 0.94-0.89 (3H, m).

Reference-Example 10N-(2-Chloro-5,6,7,8-tetrahydroquinazoline-4-yl)-N-pentylamine

The above compound was prepared according to the method ofReference-Example 9.

¹H-NMR (300 MHz, CDCl₃): δ 4.64 (1H, brs), 3.51-3.45 (2H, m), 2.68-2.65(2H, m), 2.27-2.23 (2H, m), 1.90-1.75 (4H, m), 1.70-1.55 (2H, m),1.45-1.30 (4H, m), 0.93-0.89 (3H, m).

Reference-Example 11N-(2-Chloro-5,6-dimethylpyrimidine-4-yl)-N-pentylamine

The above compound was prepared according to the method ofReference-example 9.

¹H-NMR (300 MHz, CDCl₃): δ 4.65 (1H, brs), 3.51-3.44 (2H, m), 2.34 (3H,s), 1.97 (3H, s), 1.70-1.55 (2H, m), 1.45-1.30 (4H, m), 0.94-0.89 (3H,m).

Reference-Example 12 2-Amino-5-benzyl-6-methylpyrimidine-4-ol

A mixture of ethyl 2-benzyl-3-oxobutanoate (6 g, 27.2 mmol), guanidinecarbonate (2.94 g, 16.3 mmol) and ethanol (20 ml) was refluxed for 10hours. After cooling, the precipitate was filtered and washed withwater, ethanol and ether in order, to the object compound (3.62 g,61.7%).

¹H-NMR (DMSO-d₆): d 2.01 (3H, s), 3.64 (2H, s), 6.39 (3H, brs),7.10-7.26 (5H, m), 10.89 (1H, brs).

Reference-Example 13 5-Benzyl-4-chloro-6-methylpyrimidine-2-ylamine

A mixture of 2-amino-5-benzyl-6-methylpyrimidine-4-ol (1.2 g, 5.57 mmol)and phosphorous oxychloride (9 ml) was kept to warm at 90° C. for 6hours. The reaction mixture was concentrated in vacuo. Ice-water wasadded to the residue and an aqueous ammonia was cautiously addedthereto. The solution was extracted with chloroform. The organic layerwas washed with saturated brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (chloroform: ethyl acetate=8:2) to give the objectcompound (700 mg, 53.7%).

¹H-NMR(CDCl₃): d 2.30 (3H, s) 4.05 (2H, s). 5.07 (2H, brs), 7.10-7.31(5H, m).

Reference-Example 14 2-Amino-5-phenethylpyrimidine-4-ol

Metallic sodium (966 mg, 42 mmol) was added to ether (42 ml) undernitrogen gas. Thereto a mixture of 4-phenylbutyric acid ethyl ester (8g, 42 mmol) and ethyl formate (3.42 g, 42 mmol) was dropped understirring at room temperature over a 30 minute period. The mixture wasstirred for 10 hours to prepare a ketoester compound.

Then, sodium ethoxide (3.14 g, 46.2 mmol) was added to ethanol (42 ml)under nitrogen gas. Thereto guanidine hydrochloride (4.41 g, 46.2 mmol)was added and the mixture was stirred for 30 minutes. The salt wasfiltered off and the filtrate was added to the ketoester compound inether previously prepared. The reaction mixture was kept at 80-90° for 6hours. After reaction, the solvent was removed in vacuo. A 10% aqueouscitric acid solution was added to the residue to adjust pH to 8. Ethylacetate was added to the mixture and the resulting insoluble materialwas filtered, washed with ethanol and ether to give the object compound(853 mg, 9.5%).

¹H-NMR(DMSOd₆): d 2.46 (2H, t, J=7.3), 2.73 (2H, t, J=7.3), 6.32 (2H,brs), 7.16-7.29 (5H, m), 10.88 (1H, brs).

Reference-Example 15 4-Chloro-5-phenethylpyrimidine-2-ylamine

A mixture of 2-amino-5-phenethylpyrimidine-4-ol (600 mg, 2.79 mmol) andphosphorous oxychloride (5 ml) was kept to warm at 90° C. for 6 hours.The reaction mixture was condensed in vacuo. Ice-water was added to theresidue and an aqueous ammonia was cautiously added thereto. Thesolution was extracted with chloroform. The organic layer was washedwith saturated brine, dried over sodium sulfate and concentrated invacuo. The residue was purified by silica gel column chromatography(chloroform: ethyl acetate=8:2) to give the object compound (265 mg,40.7%).

¹H-NMR(CDCl₃): d 2.87 (4H, s), 5.08 (2H, brs), 7.15-7.32 (5H, m), 7.90(1H, s).

Reference-Example 16 5-Benzyl-4-chloropyrimidine-2-ylamine

The above compound was prepared according to the method described in J.Amer. Chem. Soc., 73, 3758-3762 (1951).

Test 1

Activity on Cytokines Production From Mouse Lymph Node Cells byCompounds of Working Examples Experimental Method

1) Animals

BALB/c mice were purchased from Japan Charlse River (Yokohama) and 8weeks female mice were used.

2) Culture Medium

D-MEM (High Glucose) medium (Nikken Biomedical Research Lab. (Kyoto),Code No. CM4402) supplemented with 20% heat-inactivated (56° C., 30min.) fetal bovine serum (Characterized, Code No. A-1115-L, HyCloneLab., Logan, Utah), 50 μM 2-mercaptoethanol (Sigma, St. Louis, Mo., CodeNo. M-6250), 100 unit/ml penicillin and 100 μg/ml streptomycin(Penicillin-Streptomycin, Bibco-BRL, Code No. 15140-122) were used forthe assay.

3) Test Compounds

Each test compound dissolved in DMSO (Nacalai Tesque (Kyoto) code No.11J) at a concentration of 100 mM was diluted to final concentrationwith the medium.

4) Sensitization and Preparation of Lymph Node Cells

KLH (0.2 mg) was subcutaneously administered to mouse foot with Freund'scomplete adjuvant (Difco Lab., Detroit, Mich., Code No. 3113-60-5).Eight days later popliteal lymph node was picked up and its cellsuspension was prepared.

5) Production of Cytokine by Stimulation with an Antigen

KLH (0.1 mg/ml) and the test compound were added to lymph node cells(2.5×10⁶ cells/ml) and the mixture was incubated at 37° C. under 5% CO₂for 4 days (Corning 25850, 0.15 ml/well). Then, amount of cytokineproduced in the supernatant was measured by ELISA specific to cytokine.

Amounts of interleukin 4 (IL-4) and interleukin 5 (IL-5) as a typicalTh2 type cytokine, and amount of interferon γ (IFN-γ) as a typical Th1type cytokine were measured.

6) Method of Measurement (ELISA)

Amount of IL-4 was measured by ELISA as mentioned below. A ratanti-mouse IL-4 antibody (Pharmingen, San Diego, Calif., Code No.18031D, 0.5 mg/ml) as a primary antibody was diluted 250 times withhydrogen carbonate buffer, and it was inoculated to the 96-well plate(Falcon 3912, Becton Dickinson and Company, Flanklin Lakes, N.J.) (50/well) and each well was coated at 4° C. overnight. Then the plate wasblocked with PBS (−) solution (phosphate-buffered saline without calciumchloride and magnesium chloride) containing 3% BSA (200 μl/well). Afterrinsing the plate three times with PBS (−) solution containing 0.05%polyoxyethylene solbitan monolaurate (Tween 20™, Nacalai Tesque (Kyoto)Code No. 281-51) (PBST), the supernatant of the culture medium was addedto the wells (50 μl/well) and incubated at room temperature for 4 hours.Recombinant mouse IL-4 (Pharmingen, Code No. 19231W) was used forpreparing a calibration curve.

After rinsing the plate three times with PBST, a rat anti-mouse IL-4antibody labeled by biotin (Pharmingen, Code No. 18042D, 0.5 mg/ml) as asecondary antibody, which was diluted 500 times with PBS (−) solutioncontaining 0.1% BSA, was poured into wells (100 μl/well) . The plate wasincubated at room temperature for one hour. The secondary antibody boundto the plate was detected with streptoabidin alkaliphosphatase(Kirkegaad & Perry Lab., Gaithersburg, MD, Code No. 15-30-00) (0.25μg/ml, 100 μl/well). After incubation of the plate at 37° C. for onehour and rinsing the plate three times with PBST, the coloring was doneby adding PNPP substrate (p-nitrophenyl disodium phosphate substrate(Nacalai Tesque) (1 mg/ml, 1001 μl/well)). The absorption at 415 nm wasmeasured by a microplate reader (MTP-120 Microplate reader, CoronaElectric Co.)

Measurement of amount of IFNγ was carried out in the same method asmentioned above by using a rat anti-mouse IFNγ antibody (Pharmingen, SanDiego, Calif., Code No. 18181D, 0.5 mg/ml) as a primary antibody and arat anti-mouse IL-5 antibody labeled by biotin (Pharmingen, Code No.18112D, 0.5 mg/ml) as a secondary antibody. Recombinant mouse IFN-γ(Pharmingen, Code No. 19301U) was used for preparing a calibrationcurve.

Measurement of amount of IL-5 was carried out in the same method asmentioned above by using a rat anti-mouse IL-5 antibody (Pharmingen, SanDiego, Calif., Code No. 18051D, 0.5 mg/ml) as a primary antibody and arat anti-mouse IL-5 antibody labeled by biotin (Pharmingen, Code No.18062D, 0.5 mg/ml) as a secondary antibody. Recombinant mouse IL-5(Pharmingen, Code No. 19241W) was used for preparing a calibrationcurve. The test was carried out three times and their average wascalculated.

7) Results

Compounds of examples 10, 11, 14, 19 and 25 were used as test compoundsin this test.

Every compound was confirmed to inhibit the production of IL-4 and IL-5and to enhance the production of IFN-γ.

Test 2

Activity on Cytokines Production From Mouse Lymph Node Cells by theCompounds of Working Examples Experimental Method

In the same manner as in Test 1, each test compound dissolved in DMSO(Nacalai Tesque (Kyoto) code No. 11J) at a concentration of 100 mM wasdiluted to final concentration with the medium. Sensitization andpreparation of lymph node cells, production of cytokine by stimulationwith an antigen and measurement of amounts of cytokines were conductedin the same method as in Test 1.

By measuring inhibition rate of production of IL-4 at variousconcentrations of each test compound and using a graph relating to thecompound concentration and the inhibition rate, 50% inhibitionconcentration (IC₅₀) on each test compound was calculated.

The results were shown in Table 1.

TABLE 1 Ex. IL-4 inhibition activity Ex. IL-4 inhibition activity No.IC₅₀ (μg/ml) No. IC₅₀ (μg/ml)  1 0.6  2 0.6  3 0.5  4 3    5 0.2  6 1   7 0.5  8 1    9 1   10 0.1 11 0.1 12 1   13 10   14 0.1 15 0.4 16 3  17 5   18 0.3 19 0.2 20 0.3 21 0.5 22 0.5 23 0.5 24 0.2 25 0.1

Test 3

Activity on Cytokines Production From Mouse Lymph Node by Compounds ofWorking Examples Experimental Method and Results

In the same manner as in Test 1, each test compound dissolved in DMSO(Nacalai Tesque (Kyoto) code No. 11J) at a concentration of 100 mM wasdiluted to final concentration the medium. Sensitization and preparationof lymph cells, production of cytokine by stimulation with an en andmeasurement of amounts of cytokines were conducted in the same method asin Test 1.

As results, compounds of examples 26, 27 and 28 were confirmed toinhibit the production of IL-4 and IL-5 and to enhance the production ofIFN-γ.

Test 4

Activity on Cytokines Production From Mouse Lymph Node Cells byCompounds of Working Examples Experimental Method and Results

In the same manner as in Test 1, each test compound dissolved in DMSO(Nacalai Tesque (Kyoto) code No. 11J) at a concentration of 100 mM wasdiluted to final concentration with the medium. Sensitization andpreparation of lymph node cells, production of cytokine by stimulationwith an antigen and measurement of amounts of cytokines were conductedin the same method as in Test 1.

By measuring inhibition rate of production of IL-4 at variousconcentrations of each test compound and using a graph relating to thecompound concentration and the inhibition rate, 50% inhibitionconcentration (IC₅₀) on each test compound was calculated.

The results were shown in Table 2.

TABLE 2 IL-4 inhibition activity Ex. No. IC₅₀ (μg/ml) 26 0.5 27 1   282  

Test 5

Activity on IgE Production From Mouse In Vivo by Compounds of WorkingExamples Experimental Method

1) Animal

BALB/c mice (8 weeks female mice) were purchased from Japan CharlesRiver (Yokohama) and after pre-feeding for 9 days the mice were used.

2) Sensitization with Ovalbumin

Physiological saline solution containing ovalbumin (Sigma Chemical Co.,St Louis, Mo.) (4 μg/ml) and aluminum hydroxide·adjuvant (Alu-Gel-S;Serva Feinbiochemica GmbH & Co., Code No. 12261) were mixed in the sameamount and the mixture was intraperitoneally administered to mouse.

3) Administration Method of Test Compound

The test compound was suspended in methylcellulose, and the suspensionwas administered one hour before the sensitization with ovalubmin andonce a day for 12 days after the sensitization. Methylcellulose was usedas a control.

4) Taking Blood and Preparing Serum

On 13th day after the sensitization blood was taken from orbitalveniplex under anesthesia with a heparin treated capillary andcentrifuged to prepare serum.

5) Measurement of IgE in Blood

Measurement of IgE in blood was carried out by ELISA.

By using a rat anti-mouse IgE monoclonal antibody (Yamasa soy sauce Co.,Chiba, Code No. 7627) as a primary antibody and a biotin labeled ratanti-mouse IgE monoclonal antibody (Yamasa soy sauce Co., Chiba, CodeNo. 7617), the measurement of amount of IgE was carried out in the samemethod as in Test 2. The assay was done using the serum 500 times.Amount of IgE in blood was calculated by using standard curve of mouseIgE (Yamasa soy sauce Co., Chiba, Code No. 7626).

6) Statistic Dealing

The result was statistically dealt with t-calibration or Welchcalibration.

Test6

Activity Against Contact Hypersensitivity Reaction Induced by TNCB TestMethod

BALB/c mice (6-8 weeks female mice) were purchased from Japan CharlseRiver (Yokohama). Before use, the mice were allowed to acclimatize forone week.

2) Sensitization

Hair on mouse abdomen was cut and thereon was spread 7%2,4,6-trinitrochlorobenzene (TNCB) in acetone (0.1 ml/mouse) tosensitize.

3) Method of Measurement of Thickness of Auricula

Six days after sensitization, 1% TNCB solution in acetone was spread onboth sides of left auricula for induction. Twenty four hours laterthickness of auliculae was measured.

Value of thickness of auricula=thickness of spread leftauricula—thickness of unspread right auricula.

4) Administration Method of Test Compound

The solution prepared by dissolving a test compound (0.4 mg) in acetone(20 μl) was spread on left auricula 1-2 hours before sensitization.

INDUSTRIAL APPLICABILITY

The pyrimidine derivatives or salts thereof of the present inventionshow the activities that enhance immune responses on Th1 and suppressthe immune responses on Th2 simultaneously and further, control theimmune responses by changing the balance of Th1 and Th2. For example,they enhance production of Th1 type cytokines such as IFN-γ, etc. andinhibit production of Th2 type cytokines such as IL-4, IL-5, etc. Due tothese activities, they can be used as therapeutic and prophylacticagents for allergic diseases, parasitism, autoimmune diseases such assystemic lupus erythemathosus, virus or bacteria infectious diseases,malignant tumor, and acquired immunodeficiecy syndrome (aids).

What is claimed is:
 1. A pyrimidine compound of the formula (1) or itssalt

wherein R¹ is a formula (2)

wherein ring A is substituted or unsubstituted C₃₋₁₀ cycloalkane,substituted or unsubstituted C₅₋₁₀ cycloalkene, substituted orunsubstituted C₇₋₁₀ bicycloalkane, or substituted or unsubstitutedheterocyclic ring having an O atom or a S atom as a heteroatom, and saidS atom may form sulfinyl or sulfonyl together with one or two oxygenatoms, and R⁴ is straight or branched C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆alkinyl, C₃₋₆ cycloalkyl, C₄₋₁₀ cycloalkyl-alkyl, or OR⁸, wherein R⁸ isstraight or branched C-₁₋₁₀ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkinyl, C₃₋₆cycloalkyl or C₄₋₁₀ cycloalkyl-alkyl, or R¹ is a formula (3)

wherein R⁵ is straight or branched C₂₋₁₀ alkyl; C₂₋₆ alkenyl; C₃₋₆alkinyl; straight or branched C₁₋₁₀ alkyl substituted by hydroxy,halogen atom or C₁₋₄ alkoxy; C₃₋₈ cycloalkyl; a 5 to 7 memberedsaturated heterocyclic ring having one or two oxygen atoms asheteroatoms; or C(═O)R⁹, wherein R⁹ is straight or branched C₁₋₁₀ alkyl,C₂₋₆ alkenyl, C₃₋₆ alkinyl, C₃₋₆ cycloalkyl, C₄₋₁₀ cycloalkyl-alkyl, orOR¹⁰, wherein R¹⁰ is straight or branched C₁₋₁₀ alkyl, C₂₋₆ alkenyl,C₃₋₆ alkinyl, C₃₋₆ cycloalkyl or C₄₋₁₀ cycloalkyl-alkyl, R⁶ is ahydrogen atom, straight or branched C-₁₋₁₀ alkyl, C₆₋₁₀ aryl, halogenatom, C₆₋₁₀ aryl substituted by C₁₋₄ alkoxy or C₁₋₄ alkyl, carbamoyl, orhydroxymethyl, and R⁷ is a hydrogen atom, or straight or branched C₁₋₁₀alkyl, and R² and R³ taken together are C₃₋₅ alkylene or said alkylenein which methylene is substituted by an O atom.
 2. The pyrimidinecompound or its pharmaceutically acceptable salt of claim 1, wherein R²and R³ taken together are trimethylene or tetramethylene.
 3. Thepyrimidine compound or its pharmaceutically acceptable salt of claim 1,wherein R¹ is the formula (2)

wherein ring A and R⁴ are the same as defined above.
 4. The pyrimidinecompound or its pharmaceutically acceptable salt of claim 1, wherein R¹is the formula (3)

wherein R⁵, R⁶ and R⁷ are the same as defined above.
 5. The pyrimidinecompound or its pharmaceutically acceptable salt of claim 1 or 4,wherein R⁵ is straight C₃₋₅ alkyl or straight C₂₋₄ alkyl substituted byhydroxy.
 6. A method for suppressing the immune response of type 2helper T cells in a patient comprising administering an effective amountof the pyrimidine compound or its pharmaceutically acceptable salt ofclaim 1 as an active ingredient to said patient.
 7. A method fortreating a patient with a disease wherein suppressing the immuneresponse of type 2 helper T cells that are abnormally enhanced isnecessary to overcome said disease, comprising administering aneffective amount of the pyrimidine compound or its pharmaceuticallyacceptable salt of claim 1 to said patient.
 8. The method of claim 7,wherein the disease is an allergic disease.
 9. The method of claim 8,wherein the alleregic disease is asthma, allergic rinitis, or allergicdermatitis.
 10. A method for enhancing the immune response of type 1helper T cells in a patient comprising administering an effective amountof the pyrimidine compound or its pharmaceutically acceptable salt ofclaim 1 to a patient in need thereof.
 11. A method for enhancing theproduction of IFNγ in a patient comprising administering an effectiveamount of the pyrimidine compound or its pharmaceutically acceptablesalt of claim 1 to a patient in need thereof.
 12. A method for treatinga patient with a disease wherein enhancing the immune response of type 1helper T cells is necessary to overcome said disease, comprisingadministering an effective amount of the pyrimidine compound or itspharmaceutically acceptable salt of claim 1 to said patient.
 13. Themethod of claim 12, wherein the disease is viral or bacterial infectiousdisease.